Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Amendment
In the reply filed on 06/27/2025, Applicant has newly canceled claims 20-22 and 32-35.
Election/Restriction
Applicant’s election, without traverse, of Group I, claims 1-14, drawn to an engineered immune effector cell in which endogenous TDAG8 (GPR65) is engineered to be reduced or inhibited in expression, and election of species of engineered antigen receptor cited in claims 5-9, in the reply filed on 06/27/2025 is acknowledged.
Claim 10 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claim Status
Claims 1-14 are pending.
Claim 10 is withdrawn.
Claims 1-9 and 11-14 are considered on the merits.
Priority
This application is a 371 of PCT/US2021/013980 (filed on 01/19/2021), which claims benefit from application 62/963,121 (filed on 01/19/2020). The priority claim of the instant application has been granted and the earliest benefit date is 01/19/2020 from the application 62/963,121.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/09/2022, 02/27/2024, 01/15/2025 and 04/23/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The corresponding signed and initialed PTO forms 1449 have been mailed with this action.
Claim Objections
Claim 9 is objected to because of the following informalities:
Claim 9, line 5, recites “EGP40, ,” which contains a duplicated comma. It is recommended to change to “EGP40,”. Furthermore, Claim 9, line 5, recites both “EPCAM” and “EpCAM”. It seems like they are referring to the same antigen. It is recommended to remove one.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 and 2 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more. The claim(s) recite(s) an engineered immune effector cell which is not markedly different from its naturally occurring counterpart. This judicial exception is not integrated into a practical application because the natural product is not linked to a particular technology. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional limitations are well-understood, routine and conventional in cell biology.
Applicant is directed to the 2019 Revised Patent Subject Matter Eligibility Guidance published in the Federal Register (84 FR 50) on 1/07/2019, which is found at: https://www.govinfo.gov/content/pkg/FR-2019-01-07/pdf/2018-28282.pdf; and the October 2019 Update: Subject Matter Eligibility, which is found at https://www.uspto.gov/sites/default/files/documents/peg_oct_2019_update.pdf.
Briefly summarized here, the new guidance cites a two part test: is the claimed invention directed to a statutory class of invention (Step 1), if so then is the claimed invention as a whole directed to a law of nature, natural phenomena, natural products, or an abstract idea (i.e. set forth or described in the claim) (Step 2A, prong one), if so then is the claimed invention recite additional elements that integrate the judicial exception into a practical application (Step 2A, prong two), if not then does the claim as a whole amount to significantly more than the judicial exception (Step 2B).
In regard to Step 1, Claims 1 and 2 are drawn to a composition of matter - an engineered immune effector cell. Thus the answer here is “yes”.
In regard to Step 2A prong one, Claims 1 and 2 are drawn to a nature-based product which is not markedly different from its naturally occurring counterpart. Specifically, claims 1 and 2 are directed to an engineered immune effector cell, such as a T cell or a B cell, wherein endogenous TDAG8 (GPR65) in the cell is engineered to be reduced or inhibited in expression. These claims encompass any T cell or B cell having reduced or inhibited expression of TDAG8. This option of the claims is a naturally occurring product, as evidenced by the publication of Justus et al., (J Transl Med. 2017; 15:204, p. 1-14). Justus demonstrates that TDAG8 gene expression is reduced in immune cells in patients with blood cancers (including acute myeloid leukemia, chronic lymphocytic leukemia, follicular lymphoma, T-cell prolymphocytic leukemia with inv(14)(q11q32) and chronic B-cell lymphocytic leukemia) in comparison to healthy donor’s immune cells or leukocyte-rich tissue (see Fig 1 and legend). Thus, instant claims encompass T cells or B cells having reduced TDAG8 expression that are identical (no difference in structural or functional characteristics) to naturally occurring T cells or B cells having reduced TDAG8 expression. Furthermore, the fact that instant claims recite “engineered” cells does not differentiate them from the cells of Justus because although the claimed engineered cells may be generated by the hand of man (see [0038] in specification), they are identical to what exist in nature (i.e., having the same structure and functional characteristics). Because there is no difference between the claimed cells and naturally occurring cells in their natural state, the claimed cells do not have markedly different characteristics, and thus are a “product of nature” exception. Accordingly, instant claims are directed to a judicial exception. The answer to step 2A prong one is thus “yes”.
In regard to Step 2A prong two, the judicial exception is not integrated into a practical application. In particular, claims 1 and 2 recite no additional elements to integrate the claimed cell into a practical application to improve a technology, effect a particular treatment, or implement with a particular device to provide a meaningful limitation on the judicial exception. The answer to step 2A prong two is thus “no”.
In regard to Step 2B, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. As stated supra, claims 1 and 2 recite no additional elements to the cell. The answer to step 2B is thus “no”.
Therefore, claims 1 and 2 are directed to a natural cell product, that is not markedly different from its natural counterpart, is not integrate a practical application, and does not include elements that amount to significantly more than the natural product itself and do not qualify as patent eligible subject matter under 35 U.S.C. § 101.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3 and 14 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Radu et al., (referred to as “Radu (MCB)”. Mol Cell Biol. 2006; 26: 668-677).
With respect to claim 1, Radu (MCB) teaches a TDAG8 knockout (KO) mouse line (see e.g., Fig 1A) and teaches analysis on various immune lineages in the TDAG8 KO mice including T cells, B cells, DCs and NK cells (see e.g., Fig 3E), thus Radu (MCB) teaches an engineered immune effector cell (e.g., T cells and NK cells) wherein endogenous TDAG8 (GPR65) in the cell is engineered to be reduced in expression (i.e., TDAG8 KO that has no TDAG8 expression, see e.g., Fig 1D).
With respect to claim 2 directed to the cell being a T cell or NK cell, as stated supra, Radu (MCB) teaches T cells and NK cells from the TDAG8 KO mice (see e.g., Fig 3E), thus teaches the cell is a T cell or an NK cell.
With respect to claim 3 directed to the NK cell being derived from cord blood, it is noted that this limitation is directed to a “product-by-process” limitation. The applicant is reminded that “even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” See MPEP § 2113. In the instant case, the product itself, the NK cell of Radu (MCB) that is derived from the spleen of the TDAG8 KO mice (p. 672, left col, para 2, and Fig 3E legend), is the same as or obvious from the product in the product-by-process claim, an NK cell that is derived from cord blood. Thus, the claim is unpatentable.
With respect to claim 14 directed to the endogenous TDAG8 gene being reduced in expression from homologous recombination, Radu (MCB) teaches the TDAG8 KO mouse line is generated by homologous recombination (see p. 669, last para and Fig 1A and legend).
Accordingly, Radu (MCB) anticipates instant claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2 and 4-9 are rejected under 35 U.S.C. 103 as being unpatentable over Beavis et al., (J Clin Invest. 2017;127(3):929-941) in view of Robert et al., (Immunol Cell Biol. 2018;96(4):341-343. Cited in IDS 08/09/2022) and Radu et al., (referred to as “Radu (PNAS)”. Proc Natl Acad Sci USA. 2005;102(5):1632-1637).
With respect to claim 1, Beavis teaches targeting adenosine 2A receptor (A2AR) enhances CAR T cell efficacy (e.g., abstract) and teaches generation of A2AR-deficient CAR T cells derived from the spleen of A2AR-/- mice (see e.g., p. 933, end of 1st para and Fig 1F). Thus, Beavis teaches an engineered immune effector cell (i.e., a CAR T cell) wherein endogenous A2AR in the cell is engineered to be reduced in expression.
However, Beavis is silent on endogenous TDAG8 (GPR65) in the cell being engineered to be reduced in expression.
Nevertheless, Beavis teaches the predominant signaling pathway for the A2AR is the cAMP/PKA pathway (p. 938, right col, para 1) and teaches genetic targeting of the A2AR (such as A2AR KO) profoundly increases CAR T cell efficacy in both in vitro and in vivo tumor models and has high potential to enhance CAR T cell efficacy in several cancer types (see e.g., abstract).
Robert summarizes Gαs-coupled GPCRs in modulating immune response and teaches “the main Gαs-coupled GPCRs on immune cells are GPR65, GPR174 and A2aR. These selectively signal through Gαs which activates adenylate cyclase and results in cAMP increase” and immune cell suppression (see Fig 1 legend and p. 341, end of mid col). Robert teaches poor GPR65 signaling and less cAMP production may aid anti-tumor immune responses (p. 342, end of middle column) and teaches “(GPR65) antagonists might be of use in boosting immune responses, for immuno-oncology. Another Gαs-coupled GPCR, Adenosine A2a receptor, is a target for new immuno-oncology therapeutics” (p. 343, left col).
Radu (PNAS) teaches in thymocytes and splenocytes (i.e., mature immune cells) explanted from TDAG8 (GPR65)-KO mice, TDAG8 was found to be critical for pH-dependent cAMP production (see e.g., abstract and p. 1636, right col, 1st full para, also see Fig 7A showing exposure of WT splenocytes to pH 6.4 resulted in an 2.5- to 3-fold increase in cAMP production compared with pH 7.4. In contrast, production of cAMP by TDAG8 KO splenocytes was insensitive to pH). Radu (PNAS) teaches expression of TDAG8 by immune cells may regulate responses in acidic microenvironments such as microenvironments of many solid tumors (abstract and p. 1637, right col, 1st full para).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the CAR T cells derived from the spleen of A2AR KO mice disclosed by Beavis, by substituting the A2AR KO mice with TDAG8 (GPR65) KO mice as suggested by Robert and Radu (PNAS) with a reasonable expectation of success. Since Beavis aims to increase CAR T cell efficacy to overcome tumor-induced immunosuppression by genetically targeting the A2AR (see e.g., abstract), since Robert suggests both A2aR and GPR65 signal through Gαs resulting in cAMP increase and immunosuppression and suggests poor GPR65 signaling and less cAMP production may aid anti-tumor immune responses and acknowledges A2aR is a target for new immuno-oncology therapeutics (Fig 1 legend, p. 342, mid col and p. 343, left col), and since Radu (PNAS) teaches expression of TDAG8 by immune cells regulates responses in acidic, such as tumor microenvironments and teaches TDAG8 KO splenocytes do not have increased cAMP production in response to low pH (abstract and p. 1637, right col, 1st full para, see Fig 7A), one of ordinary skill in the art would have had a reason to generate CAR T cells derived from the TDAG8 (GPR65) KO mice as suggested by Robert and Radu (PNAS) in the method of Beavis in order to assay whether genetically targeting the TDAG8 (GPR65) would overcome tumor-induced immunosuppression and increase CAR T cell efficacy.
With respect to claim 2 directed to the cell being a T cell, as stated supra, Beavis, in view of Robert and Radu (PNAS), teaches generation of CAR T cells derived from the TDAG8 (GPR65) KO mice (see above).
With respect to claim 4 directed to the cell comprising an engineered receptor, claim 5 directed to an engineered antigen receptor, claim 6 directed to a CAR, claim 7 directed to the antigen being a cancer antigen, claim 8 directed to the antigen being a solid tumor antigen, and claim 9 directed to the antigen being HER2, Beavis teaches the CAR T cell comprises an engineered antigen receptor, i.e., a HER2 CAR (see e.g. Fig 1E), and the antigen HER2 is a cancer antigen and a solid tumor antigen that is expressed in primary melanomas (e.g., p. 930, last para), thus teaches claims 4-9.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claims 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over Beavis et al., (J Clin Invest. 2017;127(3):929-941) in view of Robert et al., (Immunol Cell Biol. 2018;96(4):341-343 Cited in IDS 08/09/2022) and Radu et al., (referred to as “Radu (PNAS)”. Proc Natl Acad Sci USA. 2005;102(5):1632-1637), as applied to claim 1 above, and further in view of Hoyos et al., (Leukemia. 2010; 24: 1160-1170).
Claims 11 and 12 are directed to the cell comprising expression of a cytokine IL-15, and claim 13 is directed to the cell comprising a suicide gene.
However, Beavis, Robert and Radu (PNAS) are silent on the cell comprising IL-15 or a suicide gene in claims 11-13.
Hoyos teaches an engineered CAR T cell comprising a CAR construct that also incorporates the interleukin-15 (IL-15) gene and an inducible caspase-9-based suicide gene (see e.g., abstract, related to claims 11-13). Hoyos teaches the CAR T cells comprising IL-15 and the suicide gene have (1) greater numeric expansion upon antigen stimulation (10-fold greater expansion in vitro, and 3- to 15-fold greater expansion in vivo) and reduced cell death rate (10% versus. 32% for control CAR T cells); (2) reduced expression of the programmed death 1 (PD-1) receptor upon antigen stimulation (PD-1+ cells <15% versus >40% for control); and (3) improved antitumor effects in vivo (from 4.7- to 5.4-fold reduced tumor growth). In addition, the CAR T cells are efficiently eliminated upon pharmacologic activation of the suicide gene. (see e.g., abstract). Hoyos teaches these IL-15-engineered T cells have superior survival, expansion and antitumor activity in vivo and the incorporation of an inducible suicide gene increases the safety of the proposed approach (p. 1167, 1st para in Discussion).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the TDAG8 KO CAR T cells suggested by Beavis in view of Robert and Radu (PNAS), by combining an IL-15 and a suicide gene as taught by Hoyos with a reasonable expectation of success. Since Hoyos teaches the IL-15-engineered CAR T cells have superior survival, expansion and antitumor activity in vivo and the incorporation of an inducible suicide gene increases the safety of the CAR T therapeutic approach (abstract and p. 1167, 1st para in Discussion), one of ordinary skill in the art would have had a reason to combine an IL-15 and a suicide gene in the TDAG8 KO CAR T cells in order to take advantage of the superior survival, expansion and antitumor activity as well as the safety of the CAR T cell therapy as taught by Hoyos.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Provisional Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-9 and 11-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims of copending Application Nos. 17/755,887, 17/756,078, 17/758,094, 17/904,408, 18/552,727, 18/560,791 or 18/574,539. Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims in the copending applications recite an engineered immune effector cells (such as an NK cell) wherein the cell is engineered to disrupt an inhibitory gene comprising TDAG8. The NK cell is derived from cord blood and comprises an antigen receptor such as a CAR targeting a tumor associated antigen. The immune cell comprises a suicide gene such as Caspase 9.
The difference between the cited application claims and the instant claims lies in the fact that the cited application claims are much more specific. Thus the invention of said claims of the cited applications are in effect “species” of the “generic” invention of the instant claims. It has been held that the generic invention is “anticipated” by the “species”. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
Since the instant application claims are anticipated by cited application claims, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631